Increased High Molecular Weight FGF2 in Endocrine-Resistant Breast Cancer

FIGUEROA, VIRGINIA; RUBSTEIN, ADRIÁN; ELÍA, ANDRÉS; ÁLVAREZ, MICHELLE M.; HEWITT, STEPHEN; LAMB, CAROLINE A.; MAY, MARÍA; FUENTES, CYNTHIA; ROJAS, PAOLA; GONZÁLEZ, PEDRO; MOLINOLO, ALFREDO; SAHORES, ANA; LIGUORI, MARCOS; JACOBSEN, BRITTA M.; SEQUEIRA, GONZALO R.; GASS, HUGO; LANARI, CLAUDIA; FIGUEROA, VIRGINIA; RUBSTEIN, ADRIÁN; MAY, MARÍA; ELÍA, ANDRÉS; FUENTES, CYNTHIA; ÁLVAREZ, MICHELLE M.; ROJAS, PAOLA; HEWITT, STEPHEN; GONZÁLEZ, PEDRO; LAMB, CAROLINE A.; MOLINOLO, ALFREDO; SAHORES, ANA; LIGUORI, MARCOS; JACOBSEN, BRITTA M.; SEQUEIRA, GONZALO R.; GASS, HUGO; LANARI, CLAUDIA

Hormones and Cancer

Springer US

Año: 2018 vol. 9 p. 338 - 348

1868-8497

Endocrine resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios. We performed lentiviral infections of different FGF2 isoforms using the human hormone-responsive T47D-YA cells, engineered to only express PRA, and evaluated tumor growth, metastatic dissemination, and endocrine responsiveness. We assessed FGF2 expression and localization in 81 human breast cancer samples. Antiprogestin-resistant experimental mammary carcinomas with low PRA/PRB ratios and T47D-YB cells, which only express PRB, displayed higher levels of HMW-FGF2 than responsive variants. HMW-FGF2 overexpression in T47D-YA cells induced increased tumor growth, lung metastasis, and antiprogestin resistance compared to control tumors. In human breast carcinomas categorized by their PRA/PRB ratio, we found nuclear FGF2 expression in 55.6% of tumor cells. No differences were found between nuclear FGF2 expression and Ki67 proliferation index, tumor stage, or tumor grade. In low-grade tumor samples, moderate to high nuclear FGF2 levels were associated to carcinomas with low PRA/PRB ratio. In conclusion, we show that HMW-FGF2 isoforms are PRB targets which confer endocrine resistance and are localized in the nuclei of breast cancer samples. Hence, targeting intracellular FGF2 may contribute to overcome tumor progression.